S102: LUSPATERCEPT VERSUS EPOETIN ALFA FOR TREATMENT (TX) OF ANEMIA IN ESA-NAIVE LOWER-RISK MYELODYSPLASTIC SYNDROMES (LR-MDS) PATIENTS (PTS) REQUIRING RBC TRANSFUSIONS: DATA FROM THE PHASE 3 COMMANDS STUDY
Authors: Matteo Giovanni Della Porta, Uwe Platzbecker, Valeria Santini, Amer M. Zeidan, Pierre Fenaux, Rami S. Komrokji, Jake Shortt, David Valcárcel, Anna Jonášová, Sophie Dimicoli-Salazar, Ing Soo Tiong, Chien-Chin Lin, Jiahui LI, Jennie Zhang, Ana Carolina Giuseppi, Sandra Kreitz, Veronika Pozharskaya, Karen L. Keeperman, Shelonitda Rose, Jeevan K. Shetty, Sheida Hayati, Sadanand Vodala, Andrius Degulys, Stefania Paolini, Thomas Cluzeau, Guillermo Garcia-Manero
Journal: HemaSphere (2023)

Topic: 10. Myelodysplastic syndromes - Clinical Background: LR-MDS pts who require RBC transfusions experience chronic anemia, increased morbidity, iron overload, and poor overall survival. The current standard tx, erythropoiesis-stimulating agents (ESAs), is suboptimal as many pts are ineligible or have limited and/or transient responses. There is an unmet need for effective tx of anemia due to LR-MDS. Luspatercept is approved in the US and EU to treat anemia in LR-MDS following ESA failure and until now has not been directly compared with ESAs in ESA-naive pts. Aims: To report interim efficacy and safety data from the phase 3, open-label, randomized COMMANDS trial (NCT03682536) comparing luspatercept with epoetin alfa in ESA-naive LR-MDS pts. Methods: Eligible pts were ≥18 y old, had serum erythropoietin (sEPO) <500 U/L, and required RBC transfusions. Pts received subcutaneous luspatercept (1.0–1.75 mg/kg; once every 3 wk) or epoetin alfa (450–1050 IU/kg; weekly) for ≥24 wk. Pts were stratified by baseline (BL) RBC transfusion burden (<4 vs ≥4 RBC U/8 wk), BL sEPO (≤200 vs >200 U/L), and RS status (RS+, RS−). The primary endpoint was the proportion of pts who were RBC transfusion independent (RBC-TI) ≥12 wk with a concurrent mean hemoglobin increase ≥1.5 g/dL during wk 1–24. Secondary endpoints included hematologic improvement-erythroid (HI-E) ≥8 wk, RBC TI 24 wk, and ≥12 wk in wk 1–24, as well as subgroup analyses, impact of MDS-associated gene mutations on response, and safety. Results: 178 pts were randomized to luspatercept and 178 to epoetin alfa (31Aug2022); median tx durations were 41.6 and 27.0 wk, respectively. BL characteristics were balanced between arms. The primary endpoint was achieved by 86/147 (58.5%) luspatercept and 48/154 (31.2%) epoetin alfa pts (P<0.0001; Fig. A); primary endpoint achievement favored luspatercept or was similar to epoetin alfa for all subgroups (Fig. B). Luspatercept tx also favored achievement of HI-E ≥8 wk, RBC-TI 24 wk, and RBC-TI ≥12 wk in wk 1–24 (Fig. A). Median duration of RBC-TI ≥12 wk (wk 1 to end of tx) was longer with luspatercept vs epoetin alfa tx overall (126.6 and 77.0 weeks, respectively), and for clinically relevant subgroups, including RS+ and RS−. Pts with SF3B1, SF3B1α, ASXL1, TET2, DNMT3A, EZH2, IDH2, and U2AF1 mutations also demonstrated favorable luspatercept response vs epoetin alfa (Fig. C). Luspatercept pts had a higher probability of achieving clinical benefit, regardless of overall mutational burden. 164 (92.1%) luspatercept and 150 (85.2%) epoetin alfa pts reported tx-emergent adverse events (TEAEs) of any grade; 8 (4.5%) and 4 (2.3%) pts discontinued tx due to TEAEs. The most common TEAEs (any grade) with luspatercept were fatigue (14.6%), diarrhea (14.6%), and hypertension (12.9%), and with epoetin alfa were asthenia (14.2%), diarrhea (11.4%), and anemia (9.7%). The most common TEAEs in luspatercept pts were mild to moderate, non-serious, and generally did not lead to discontinuation. 4 (2.2%) luspatercept and 5 (2.8%) epoetin alfa pts progressed to AML; overall death rates were similar between arms (32 [18.0%] vs 32 [18.2%], respectively). Summary/Conclusion: Luspatercept demonstrated superiority over epoetin alfa with clinically meaningful improvements in RBC-TI and HI-E rates in ESA-naive LR-MDS pts who require transfusions. Luspatercept showed more favorable outcomes compared to epoetin alfa across a spectrum of known MDS mutations. Luspatercept safety profile was comparable with previous reports; no new safety events were identified. Luspatercept may transform the current landscape by establishing a new standard of tx for ESA-naive pts with transfusion dependent LR-MDS.Keywords: Mutation analysis, Myelodysplastic syndrome, Erythropoieisis, Clinical trial